Collagenous colitis was first described by Lindstrom as chronic watery diarrhea (Pathol Eur 11(1):87-89, 1976). Collagenous colitis is characterized by collagen deposition, likely resulting from an imbalance between collagen production by mucosal fibroblasts and collagen degradation. Very little is understood, however, regarding the mechanism by which collagenous colitis results in secretory diarrhea.
The incidence of collagenous colitis is similar to primary biliary cirrhosis. This disease has an annual incidence of 1.8 per 100,000 and a prevalence of 15.7 per 100,000, which is similar to primary biliary cirrhosis (12.8 per 100,000) and lower than ulcerative colitis (234 per 100,000), Crohn's disease (146 per 100,000) or celiac disease (5 per 100,000). In patients with chronic diarrhea, about 0.3 to 5% have ollagenous colitis.
In efforts to characterize the patients under study, sera and monocyte conditioned media (MCM) from patients with collagenous colitis have been assessed for their ability to stimulate fibroproliferation. Cytokine antibodies were used to characterize the fibroproliferative component of patient samples.
Previous studies have suggested that MCM samples obtained from patients with liver disease are capable of stimulating proliferation of fibroblasts (see Peterson and Isbrucker, in Hepatol. 15(2):191-197, 1992). It has also been established that several genes involved in proliferation possess AP-1 binding sites, and thus would be expected to be susceptible to regulation by the immediate early genes c-fos and c-jun (see, for example, Schafer et al., in Biochem Biophys Res Commun 221:111-116, 1996) and Bamberger et al., in Proc Nat Acad Sci. USA 9:6169-6174, 1996).
In order to determine whether these immediate early genes are upregulated by MCM obtained from patients with liver disease, the effect of MCM from patients with liver disease was investigated. MCM exerts many effects due to PDGF (see, for example, Peterson and Isbrucker, supra, 1992) and Peterson and Tanton in Can. J. Gastroenterol. 10:S76 1996)). Indeed, it has been established that PDGF itself stimulates proliferation of fibroblasts (see T. C. Peterson, in Hepatol. 173):486-493, 1993) and Peterson et al., in Immunopharmacol. 28:259-270, 1994). Thus, the question of whether PDGF upregulates the expression of c-fos and c-jun was addressed.
Prior studies have indicated that pentoxifylline inhibits PDGF and MCM stimulated proliferation (see, for example, T. C. Peterson, supra, 1993), Peterson et al., in Immunopharmacol. 28:259-270, 1994) and Peterson and Neumeister in Immunopharmacol. 31:183-193, 1996)). The mechanism for this effect of pentoxifylline remains unclear, but does not appear to involve competing for the PDGF receptor or adenosine receptor activation (see T. C. Peterson, in Biochem Pharmacol 52:597-602, 1996)).
It is known that c-Jun forms heterologous signaling protein combinations with a number of entities. For instance, c-Jun forms heterologous signaling protein complexes with ATF2 (Y. Sano, et al., J Biol Chem, 273(44):29098-105, 1998) and the activity of ATF2 is enhanced after phosphorylation occurs with c-Jun N-terminal kinase. Recent evidence also suggests that linkage between ATF2 and c-Jun is important in expression of cyclin kD1, a gene of critical importance in breast tumors where over-expression of cyclin D1 gene has been implicated (R. Lee, et al., J Biol Chem, 274(11):7341-50, 1999).
c-Jun also forms a complex with CREB. This protein complex plays a particularly important role in TNF.alpha. gene expression. TNF.sub..alpha. expression has been implicated in endotoxic shock, multiple sclerosis, cerebral malaria and other inflammatory diseases (Delgado-M, Munoz-Elias-Ej, Kan-Y, Gozes-I, Fridkin-M, Brenneman-D E, Gomariz-R P, Ganea-D, J-Biol-Chem 273(47):31427-36,1998). The complex CREB/c-Jun has also been implicated in squamous cell differentiation and plays a role in transglutaminase I activity in tracheal epithelial cells (A. Medvedev, et al., J Biol Chem, 274(6):3887-96, 1999).
Another example of a c-Jun complex associated with disease is the Nrf1 complex with c-Jun. The Nrf1/c-Jun complex is associated with signaling by the TNF.sub..alpha. promoter in stimulated mast cells (V. Novotny, et al., Nucleic Acids Res, 26(23):5480-5, 1998).
Accordingly, in view of the numerous combinations in which c-Jun participates, there is a need in the art to achieve a better understanding of the mechanism by which c-Jun and complexes of c-Jun with signaling proteins contribute to fibrotic proliferative disorders and for methods of treatment of such diseases.